The project goal is to quantify the roles and interactions of stimulus charge density (QD) and charge per phase (Q) in the induction of depression of neuronal excitability and loss of neurons during prolonged microstimulation in the cerebral cortex. We will examine these effects of the microstimulation in the immediate vicinity of the stimulating microelectrodes in the feline post-cruciate gyrus of the cerebral cortex, and also the remote effects in the adjacent pre-cruciate gyrus. The relations between Q, QD and the occurrence (or absence) of neuronal injury have been determined for larger macroelectrodes and has enabled development of protocols for safe and effective electrical stimulation with neural interfaces, and we propose to do the same for intraparenchymal microstimulation. Safe (and damaging) protocols for intraparenchymal microstimulation have been determined for some specific situations, but for microstimulation a systematic study has not been performed for the interactions of Q,QD and the physiologic and histologic responses. The proposed study will employ silicon substrate microelectrodes and microwire electrodes implanted chronically in the sensorimotor cortex of adult cats. We will identify combinations of Q and QD that are able to excite pyramidal tract neurons of the cerebral cortex without producing depression of neuronal excitability or loss during 200 hours of stimulation (8 hrs/day for 25 days). The range of Q to be evaluated (2 to 16 nC/phase) will span all or most of the range that is likely to be used in a clinical interface. The stimulus will be delivered for 7 hour per day, for a total of 210 hours at a pulse rate of 50 pps. This is intended to be a realistic representative of the parameters that would be used in a clinical neural interface. Since Q/QD = A, the electrodes' geometric surface area, the data from the study will define the value of A that is necessary and sufficient to allow safe and effective chronic microstimulation in the cerebral cortex using a specified charge per phase.